Pyrazol compounds as eaat3 inhibitors

ABSTRACT

The invention provides novel compounds having the general formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 1′ , R 2 , R 3 , R 4  are as defined herein, compositions including the compounds and methods of using the compounds.

The present invention relates to organic compounds useful for therapy orprophylaxis in a mammal, and in particular to EAAT3 inhibitors for thetreatment or prophylaxis of EAAT3 mediated diseases, such as psychiatricdisorders such as schizophrenia, bipolar disorder, obsessive-compulsivedisorder or autism spectrum disorder.

The present invention provides novel compounds of formula (I)

wherein

-   -   R^(1′) is methyl;    -   R¹ is selected from the group consisting of        -   i) methyl,        -   ii) ethyl,        -   iii) trifluoromethyl        -   iv) hydroxymethyl,        -   v) cyclopropyl, and        -   vi) cyano;    -   or R^(1′) and R¹ together with the carbon atom to which they are        attached form 1,1-dioxo-tetrahydro-thiophen-3-yl;    -   R² is selected from the group consisting of        -   i) hydrogen,        -   ii) methyl,        -   iii) ethyl,        -   iv) isopropyl,        -   v) tert-butyl,        -   vi) cyclopropyl,        -   vii) cyclopropylmethyl, and        -   viii) hydroxymethyl;    -   R³ is selected from the group consisting of        -   i) hydrogen,        -   ii) chloro,        -   iii) fluoro,        -   iv) methyl        -   v) isopropyl,        -   vi) methoxy,        -   vii) cyano,        -   viii) cyclopropyl, and        -   ix) trifluoromethyl;    -   R⁴ is selected from the group consisting of        -   i) hydrogen,        -   ii) chloro,        -   iii) fluoro, and        -   iv) methyl;    -   or pharmaceutically acceptable salts.

It has been surprisingly been found that the compounds of generalformula I are EAAT3 inhibitors.

The excitatory amino acid transporter 3 (EAAT3), also referred to inhuman studies as solute carrier family 1, member 1 (systematic genename: SLC1A1) and in rodents as excitatory amino acid carrier 1 (EAAC1),is a high-affinity anionic amino acid transporter found in neuronsthroughout the cortex and in the hippocampus, basal ganglia (striatum,thalamus), and the olfactory bulb. EAAT3 functions to buffer localglutamate concentrations at excitatory synapses, for example in thehippocampus, and modulates the differential recruitment of glutamatereceptor subtypes at extrasynaptic sites. Furthermore, EAAT3 is thoughtto be involved in facilitating GABA and glutathione biosynthesis. EAAT3is a member of the EAAT family that mediates the uptake of glutamateinto neuronal and glial cells of the mammalian CNS. Two transportersexpressed primarily in glia, EAAT1 and EAAT2, are crucial for glutamatehomeostasis in the adult mammalian brain and for rapid clearance ofglutamate from the synaptic cleft. Three neuronal transporters (EAAT3,EAAT4, and EAAT5) appear to have additional functions in regulating andprocessing cellular excitability with EAAT3 being abundantly expressedthroughout the CNS (EAAT4 is unique to Purkinje cells of the cerebellumand EAAT5 is expressed in rod photoreceptor and bipolar cells of theretina).

EAATs are assembled as trimers, and the existence of multiple isoformsraises the question of whether certain isoforms can formhetero-oligomers. In the mammalian brain, the specificity of excitatorysynaptic transmission depends on rapid diffusion of glutamate away fromactive synapses and the powerful uptake capacity of glutamatetransporters in astrocytes. The extent to which neuronal glutamatetransporters influence the lifetime of glutamate in the extracellularspace remains unclear, but it is thought to be minor. EAAT3, thepredominant neuronal glutamate transporter at excitatory synapses inhippocampal area CA1, buffers glutamate released during synaptic eventsand prolongs the time course of its clearance by astrocytes. EAAT3 doesnot significantly alter activation of receptors in the synaptic cleft.Instead, it reduces recruitment of perisynaptic/extrasynapticNR2B-containing NMDARs, thereby facilitating induction of long-termpotentiation by short bursts of high-frequency stimulation. SpecificEAAT3 inhibitors may have the potential to locally and specificallystrengthen particular synapses.

Obsessive-compulsive disorder (OCD) is among the most common mentaldisorders (prevalence 1-3%), and is at least as prevalent asschizophrenia and bipolar disorder. In the United States, one in 50adults suffers from OCD. OCD affects children and adolescents as well asadults. Roughly one third to one half of adults with OCD reports achildhood onset of the disorder, and the disorder is typically chronicin nature. Treatment consists of predominantly serotonergic TCAs(clomipramine) or SSRIs in combination with cognitive-behavioral therapy(CBT). Overall, response to these interventions is of some but stilllimited benefit (approximately comparable to antidepressant response inMDD), and given the chronicity of OCD, the unmet medical need remainsvery high. OCD has been linked to serotonin and glutamate abnormalities.The hypothesis of glutamate signaling dysfunction in OCD is based onfindings from neuroimaging, animal models, positional cloning andtreatment studies.

The obsessive-compulsive symptomatology in OCD has considerablephenomenological, epidemiological and possibly(aetio)-pathophysiological overlap with a core autism spectrum disordercriterion: “restricted, repetitive patterns of behavior, interests, oractivities” (taken from proposed DSM-5 revision). In support of thisnotion, human genetics studies have linked both the serotonintransporter and EAAT3 (SLC1A1) genes to autism spectrum disorder (ASD)or rigid-compulsive behavior in ASD and to OCD.

In addition, obsessive-compulsive symptoms induced by antipsychotics inschizophrenic bipolar disorder patients have been linked to EAAT3(SLC1A1) gene variants. Post-mortem brain studies have shown that bothclassic and atypical antipsychotics reduce EAAT3, suggesting aninvolvement of this transporter in neuroleptic mechanisms beyonddopamine and serotonin modulation. Moreover, genetic variation in thehuman gene EAAT3 (SLC1A1) has been associated with antipsychotic drugresponse.

There is converging evidence from neurobiological data, human genetics,imaging studies and experimental treatments that EAAT3 is a keypathophysiological element in OCD and rigid-compulsive behavior inautism and in schizophrenia.

-   Curr. Opin. Pharmacol. 20, 116-123, 2015-   J. Neurosci., 32, 2552-2563, 2012-   J. Neurosci 29, 14581-14595, 2009-   Arch. Gen. Psychiatry, 66, 408-416, 2009-   Pharmacol. Ther. 107, 271-285, 2005-   J. Neurochem. 98, 1007-1018, 2006-   Nat. Neurosci., 9, 119-126, 2006

Objects of the present invention are the compounds of formula (I) andtheir aforementioned salts and esters and their use as therapeuticallyactive substances, a process for the manufacture of the said compounds,intermediates, pharmaceutical compositions, medicaments containing thesaid compounds, their pharmaceutically acceptable salts or esters, theuse of the said compounds, salts or esters for the treatment orprophylaxis of disorders or conditions that are associated with theactivity of EAAT3, particularly in the treatment or prophylaxis ofpsychiatric disorders such as schizophrenia, bipolar disorder,obsessive-compulsive disorder or autism spectrum disorder, and the useof the said compounds, salts or esters for the production of medicamentsfor the treatment or prophylaxis of psychiatric disorders such asschizophrenia, bipolar disorder, obsessive-compulsive disorder or autismspectrum disorder.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, in particular hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleicacid, malonic acid, succinic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,N-acetylcystein and the like. In addition, these salts may be preparedby addition of an inorganic base or an organic base to the free acid.Salts derived from an inorganic base include, but are not limited to,the sodium, potassium, lithium, ammonium, calcium, magnesium salts andthe like. Salts derived from organic bases include, but are not limitedto salts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine, lysine,arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.Particular pharmaceutically acceptable salts of compounds of formula (I)are the hydrochloride salts, methanesulfonic acid salts and citric acidsalts.

“Pharmaceutically acceptable esters” means that compounds of generalformula (I) may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundsin vivo. Examples of such compounds include physiologically acceptableand metabolically labile ester derivatives, such as methoxymethylesters, methylthiomethyl esters and pivaloyloxymethyl esters.Additionally, any physiologically acceptable equivalents of thecompounds of general formula (I), similar to the metabolically labileesters, which are capable of producing the parent compounds of generalformula (I) in vivo, are within the scope of this invention.

The term “protecting group” (PG) denotes a group which selectivelyblocks a reactive site in a multifunctional compound such that achemical reaction can be carried out selectively at another unprotectedreactive site in the meaning conventionally associated with it insynthetic chemistry. Protecting groups can be removed at the appropriatepoint. Exemplary protecting groups are amino-protecting groups,carboxy-protecting groups or hydroxy-protecting groups.

Particular protecting groups are the tert-butoxycarbonyl (Boc),benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn)groups. Further particular protecting groups are the tert-butoxycarbonyl(Boc) and the fluorenylmethoxycarbonyl (Fmoc) groups. More particularprotecting group is the tert-butoxycarbonyl (Boc) group.

The abbreviation uM means microMolar and is equivalent to the symbol μM.

The abbreviation uL means microliter and is equivalent to the symbol μL.

The abbreviation ug means microgram and is equivalent to the symbol μg.

The compounds of formula (I) can contain several asymmetric centers andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates.

According to the Cahn-Ingold-Prelog Convention the asymmetric carbonatom can be of the “R” or “S” configuration.

Also an embodiment of the present invention are compounds according toformula (I) as described herein and pharmaceutically acceptable salts oresters thereof, in particular compounds according to formula (I) asdescribed herein and pharmaceutically acceptable salts thereof, moreparticularly compounds according to formula (I) as described herein.

A particular embodiment of the present invention provides compoundsaccording to formula (I) as described herein, wherein R¹ is methyl

A particular embodiment of the present invention provides compoundsaccording to formula (I) as described herein, wherein R² is selectedfrom the group consisting of

-   -   i) methyl,    -   ii) ethyl,    -   iii) isopropyl,    -   iv) tert-butyl,    -   v) cyclopropyl, and    -   vi) cyclopropylmethyl.

A particular embodiment of the present invention provides compoundsaccording to formula (I) as described herein, wherein R³ is selectedfrom the group consisting of

-   -   i) hydrogen,    -   ii) chloro,    -   iii) fluoro,    -   iv) methyl    -   v) isopropyl,    -   vi) methoxy,    -   vii) cyano,    -   viii) cyclopropyl, and    -   ix) trifluoromethyl.

A further particular embodiment of the present invention providescompounds according to formula (I) as described herein, wherein R³ isselected from the group consisting of

-   -   i) chloro,    -   ii) fluoro,    -   iii) cyano, and    -   iv) trifluoromethyl.

A particular embodiment of the present invention provides compoundsaccording to formula (I) as described herein, wherein R⁴ is H.

A more particular embodiment of the present invention provides compoundsaccording to formula (I) as described herein, wherein

R^(1′) and R¹ are both methyl;

R² is selected from the group consisting of

-   -   i) methyl,    -   ii) ethyl,    -   iii) isopropyl,    -   iv) tert-butyl,    -   v) cyclopropyl, and    -   vi) cyclopropylmethyl;

R³ is selected from the group consisting of

-   -   i) hydrogen,    -   ii) chloro,    -   iii) fluoro,    -   iv) methyl    -   v) isopropyl,    -   vi) methoxy,    -   vii) cyano, and    -   viii) cyclopropyl

R⁴ is selected from the group consisting of

-   -   i) hydrogen,    -   ii) chloro,    -   iii) fluoro, and    -   iv) methyl;    -   or pharmaceutically acceptable salts.

Particular examples of compounds of formula (I) as described herein areselected from

-   N-tert-butyl-3-(4-chlorophenyl)-5-(2-methylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-fluorophenyl)benzamide;-   N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-[4-(trifluoromethyl)phenyl]benzamide;-   N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-chlorophenyl)benzamide;-   N-tert-butyl-3-(4-chlorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(4-fluorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(2-propan-2-ylpyrazol-3-yl)-5-[4-(trifluoromethyl)phenyl]benzamide;-   N-tert-butyl-3-(3,4-difluorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(4-methylphenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(4-propan-2-ylphenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(4-methoxyphenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(3-chloro-4-fluorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-phenyl-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(4-cyclopropylphenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(4-fluoro-3-methylphenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(4-chloro-3-fluorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(4-cyanophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   3-(2-tert-butylpyrazol-3-yl)-5-(4-chlorophenyl)-N-(2-methylbutan-2-yl)benzamide;-   3-(4-chlorophenyl)-N-(2-methylbutan-2-yl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(3-fluoro-4-methylphenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   3-(4-chlorophenyl)-N-(2-cyanopropan-2-yl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   3-(2-tert-butylpyrazol-3-yl)-5-(4-chlorophenyl)-N-(2-cyanopropan-2-yl)benzamide;-   N-tert-butyl-3-(2-cyclopropylpyrazol-3-yl)-5-(4-fluorophenyl)benzamide;-   N-tert-butyl-3-(4-chlorophenyl)-5-(2-ethylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(4-chlorophenyl)-5-[2-(cyclopropylmethyl)pyrazol-3-yl]benzamide;-   3-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-fluoro-3-methylphenyl)benzamide;-   N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-phenylbenzamide;-   N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(3-fluoro-4-methylphenyl)benzamide;-   N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-methylphenyl)benzamide;-   N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-methoxyphenyl)benzamide;-   N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(3-chloro-4-fluorophenyl)benzamide;-   N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-chloro-3-fluorophenyl)benzamide;-   N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-propan-2-ylphenyl)benzamide;-   3-(2-tert-butylpyrazol-3-yl)-5-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)benzamide;-   N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(3,4-difluorophenyl)benzamide;-   N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-cyclopropylphenyl)benzamide;-   N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-cyanophenyl)benzamide;-   3-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   3-(4-chlorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide;-   3-(2-tert-butylpyrazol-3-yl)-5-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)benzamide;-   3-(2-tert-butylpyrazol-3-yl)-5-(4-chlorophenyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide;-   N-tert-butyl-3-(2-cyclopropylpyrazol-3-yl)-5-[4-(trifluoromethyl)phenyl]benzamide;-   N-tert-butyl-3-[2-(cyclopropylmethyl)pyrazol-3-yl]-5-[4-(trifluoromethyl)phenyl]benzamide;-   N-tert-butyl-3-(4-chlorophenyl)-5-(2-cyclopropylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-[2-(cyclopropylmethyl)pyrazol-3-yl]-5-(4-fluorophenyl)benzamide;-   N-tert-butyl-3-(2-ethylpyrazol-3-yl)-5-(4-fluorophenyl)benzamide;-   N-tert-butyl-3-(2-ethylpyrazol-3-yl)-5-[4-(trifluoromethyl)phenyl]benzamide;

and pharmaceutically acceptable salts thereof.

Further particular examples of compounds of formula (I) as describedherein are selected from

-   N-tert-butyl-3-(4-chlorophenyl)-5-(2-methylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-fluorophenyl)benzamide;-   N-tert-butyl-3-(4-chlorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(4-fluorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(2-propan-2-ylpyrazol-3-yl)-5-[4-(trifluoromethyl)phenyl]benzamide;-   N-tert-butyl-3-(2-cyclopropylpyrazol-3-yl)-5-(4-fluorophenyl)benzamide;-   N-tert-butyl-3-(4-chlorophenyl)-5-(2-ethylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(4-chlorophenyl)-5-[2-(cyclopropylmethyl)pyrazol-3-yl]benzamide;-   N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-cyanophenyl)benzamide;-   N-tert-butyl-3-(4-chlorophenyl)-5-(2-cyclopropylpyrazol-3-yl)benzamide;-   N-tert-butyl-3-(2-ethylpyrazol-3-yl)-5-(4-fluorophenyl)benzamide;

and pharmaceutically acceptable salts thereof.

Processes for the manufacture of compounds of formula (I) as describedherein are an object of the invention.

The preparation of compounds of formula (I) of the present invention maybe carried out in sequential or convergent synthetic routes. Synthesesof the invention are shown in the following general schemes. The skillsrequired for carrying out the reactions and purifications of theresulting products are known to those persons skilled in the art. Incase a mixture of enantiomers or diastereoisomers is produced during areaction, these enantiomers or diastereoisomers can be separated bymethods described herein or known to the man skilled in the art such ase.g. (chiral) chromatography or crystallization. The substituents andindices used in the following description of the processes have thesignificance given herein.

In general the pyrazole derivatives I can either be prepared from theintermediate iodo derivatives II by coupling reaction with commerciallyavailable pyrazole boronic acids III.

or by coupling reaction of the iodo derivatives IV with commerciallyavailable boronic acid derivatives V.

The iodo derivatives II can be prepared starting from commerciallyavailable 3-iodo-5-nitrobenzoic acid VI. Amide formation with thecommercially available amines VII using standard conditions leads to theamides VIII which can coupled with commercially available boronic acidderivatives V to yield the nitro compounds IX which can be reduced withtin(II)chloride to yield the aniline derivatives X. Well knowntransformation of the aniline into iodine leads to the iodo buildingblocks II.

The synthesis of the iodo derivatives IV can start from the abovedescribed iodo derivatives VIII which can be transformed into thepyrazole derivatives XI by coupling reaction with commercially availablepyrazole boronic acids III. Reduction of the nitro group to the anilineas described above leads to the derivatives XII. The iodo derivatives IVcan be prepared from derivatives XII by known transformation of theaniline into the iodine.

An alternative route for the synthesis of the pyrazole derivatives I canstart from the commercially available 3-iodo-5-nitrobenzoic acid VI.Coupling reaction with commercially available boronic acid derivatives Vyields the nitro derivatives XII which can be transformed into the iododerivatives XIV as described above by reduction of the nitro groupfollowed by well-known transformation of the aniline into iodine, andsubsequent ester formation. The iodo derivatives XIV can be transformedinto the boronate derivatives XV by known methods. Coupling reactionwith commercially available bromo pyrazole derivatives XVI, andsubsequent ester hydrolysis by known methods yielded the acidderivatives XVII. Amide formation with the commercially available aminesVII using standard conditions leads to the final amides I.

It is also possible to prepare the final compounds I by couplingreaction of the commercially available bromo pyrazole derivatives XVIwith the boronates XVIII which can be prepared from the iodo buildingblock II by known methods.

Also an embodiment of the present invention is a process to prepare acompound of formula (I) as defined above comprising a) the reaction of acompound of formula (II) in the presence of a compound of formula (III),wherein R¹, R^(1′), R², R³ and R⁴ are as defined in any one of claim 1to 9;

or

-   -   b) the reaction of a compound of formula (IV) in the presence of        a compound of formula (V), wherein R¹, R^(1′), R², R³ and R⁴ are        as defined herein;

or

-   -   c) the reaction of a compound of formula (XVII) in the presence        of a compound of formula (VII), wherein R¹, R^(1′), R², R³ and        R⁴ are as defined in any one of claim 1 to 9;

or

-   -   d) the reaction of a compound of formula (XVIII) in the presence        of a compound of formula (XVI), wherein R¹, R^(1′), R², R³ and        R⁴ are as defined in any one of claim 1 to 9.

Also an object of the present invention is a compound according toformula (I) as described herein for use as a therapeutically activesubstance.

Likewise an object of the present invention is a pharmaceuticalcomposition comprising a compound according to formula (I) as describedherein and a therapeutically inert carrier.

A particular embodiment of the present invention is a compound accordingto formula (I) as described herein for the treatment or prophylaxis ofocular conditions, particularly glaucoma.

The present invention also relates to the use of a compound according toformula (I) as described herein for the preparation of a medicament forthe treatment or prophylaxis of ocular conditions, particularlyglaucoma.

Also an object of the invention is a method for the treatment orprophylaxis of ocular conditions, particularly glaucoma, which methodcomprises administering an effective amount of a compound according toformula (I) as described herein.

Also an embodiment of the present invention are compounds of formula (I)as described herein, when manufactured according to any one of thedescribed processes.

Assay Procedures The FLIPR Membrane Potential (FMP) Assay

HEK-293 cells stably expressing human EAAT3 were seeded at 55 000cells/well in growth medium (DMEM glutamate free (Invitrogen 11960-044),1% Pen Strep (10 ml/l GIBCO BRL N^(o) 15140-023), 10% FCS non dialysedheat inactivated, 5 mg/l puromycin) in poly-D-lysine treated 96-wellblack microtiter plates with clear-bottom. After 24 h, the growth mediumwas removed and 100 μl/well of Krebs buffer (140 mM NaCl, 4.7 mM KCl,2.5 mM CaCl₂, 1.2 mM MgCl₂, 11 mM HEPES, 10 mM D-glucose, pH=7.4) added.The cells were then loaded by adding 100 μl/well FMP assay dye (FLIPRMembrane Potential assay reagent, Molecular Devices). The 96-well plateswere then incubated at 37° C. for 1 h. The depolarization of the cellswill cause more dye to enter in the cells, where it will bind tointracellular proteins and lipids and cause an increase in thefluorescence signal. Antagonist potency at human EAAT3 was determined byusing L-glutamate as agonist at a concentration which gives 80% of themaximum response. The antagonists were applied 15 min before theapplication of the agonist L-glutamate. The assays were performed atroom temperature and measurements done by using a Fluorometric ImagingPlate Reader (FLIPR, Molecular Devices) and filter #2. Responses weremeasured as peak increase in fluorescence minus basal (i.e. fluorescencewithout addition of L-glutamate). Kb was determined using theCheng-Prusoff equation Kb=IC₅₀/[1+(A/EC₅₀)], where IC₅₀ is theconcentration of the antagonist producing 50% inhibition, A is theconcentration of the agonist against which the IC₅₀ is being determined(at EC₅₀) and EC₅₀ is the concentration of the agonist producing 50%inhibition.

EAAT3 Example Kb (μM) 1 0.24 2 0.19 3 0.28 4 0.32 5 0.17 6 0.095 7 0.188 0.39 9 0.26 10 0.55 11 0.29 12 0.61 13 0.3 14 0.88 15 1.28 16 0.31 170.33 18 3.42 19 0.89 20 0.36 21 0.32 22 0.37 23 0.11 24 0.17 25 0.25 261.52 27 0.93 28 0.47 29 0.39 30 0.37 31 0.25 32 0.41 33 0.29 34 0.6 350.92 36 0.44 37 1.13 38 0.24 39 0.27 40 0.62 41 0.26 42 0.89 43 0.32 440.4 45 0.26 46 0.28 47 0.11 48 0.29

The compounds of formula (I) and their pharmaceutically acceptable saltscan be used as medicaments (e.g. in the form of pharmaceuticalpreparations). The pharmaceutical preparations can be administeredinternally, such as orally (e.g. in the form of tablets, coated tablets,dragees, hard and soft gelatin capsules, solutions, emulsions orsuspensions), nasally (e.g. in the form of nasal sprays), rectally (e.g.in the form of suppositories) or topical ocularly (e.g. in the form ofsolutions, ointments, gels or water soluble polymeric inserts). However,the administration can also be effected parenterally, such asintramuscularly, intravenously, or intraocularly (e.g. in the form ofsterile injection solutions).

The compounds of formula (I) and their pharmaceutically acceptable saltscan be processed with pharmaceutically inert, inorganic or organicadjuvants for the production of tablets, coated tablets, dragees, hardgelatin capsules, injection solutions or topical formulations Lactose,corn starch or derivatives thereof, talc, stearic acid or its salts etc.can be used, for example, as such adjuvants for tablets, dragees andhard gelatin capsules.

Suitable adjuvants for soft gelatin capsules, are, for example,vegetable oils, waxes, fats, semi-solid substances and liquid polyols,etc.

Suitable adjuvants for the production of solutions and syrups are, forexample, water, polyols, saccharose, invert sugar, glucose, etc.

Suitable adjuvants for injection solutions are, for example, water,alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural orhardened oils, waxes, fats, semi-solid or liquid polyols, etc.

Suitable adjuvants for topical ocular formulations are, for example,cyclodextrins, mannitol or many other carriers and excipients known inthe art.

Moreover, the pharmaceutical preparations can contain preservatives,solubilizers, viscosity-increasing substances, stabilizers, wettingagents, emulsifiers, sweeteners, colorants, flavorants, salts forvarying the osmotic pressure, buffers, masking agents or antioxidants.They can also contain still other therapeutically valuable substances.

The dosage can vary in wide limits and will, of course, be fitted to theindividual requirements in each particular case. In general, in the caseof oral administration a daily dosage of about 0.1 mg to 20 mg per kgbody weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g.about 300 mg per person), divided into preferably 1-3 individual doses,which can consist, for example, of the same amounts, should it beappropriate. In the case of topical administration, the formulation cancontain 0.001% to 15% by weight of medicament and the required dose,which can be between 0.1 and 25 mg in can be administered either bysingle dose per day or per week, or by multiple doses (2 to 4) per day,or by multiple doses per week It will, however, be clear that the upperor lower limit given herein can be exceeded when this is shown to beindicated.

Preparation of Pharmaceutical Compositions Comprising Compounds of theInvention:

Tablets of the following composition are manufactured in the usualmanner:

mg/tablet ingredient 5 25 100 500 Compound of formula I 5 25 100 500Lactose Anhydrous DTG 125 105 30 150 Sta-Rx 1500 6 6 6 60Microcrystalline Cellulose 30 30 30 450 Magnesium Stearate 1 1 1 1 Total167 167 167 831

Manufacturing Procedure

-   1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.-   2. Dry the granules at 50° C.-   3. Pass the granules through suitable milling equipment.-   4. Add ingredient 5 and mix for three minutes; compress on a    suitable press.

Capsules of the Following Composition are Manufactured:

mg/capsule ingredient 5 25 100 500 Compound of formula I 5 25 100 500Hydrous Lactose 159 123 148 — Corn Starch 25 35 40 70 Talk 10 15 10 25Magnesium Stearate 1 2 2 5 Total 200 200 300 600

Manufacturing Procedure

-   1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.-   2. Add ingredients 4 and 5 and mix for 3 minutes.-   3. Fill into a suitable capsule.

A compound of formula I lactose and corn starch are firstly mixed in amixer and then in a comminuting machine. The mixture is returned to themixer; the talc is added thereto and mixed thoroughly. The mixture isfilled by machine into suitable capsules, e.g. hard gelatin capsules.

Injection Solutions of the Following Composition are Manufactured:

ingredient mg/injection solution. Compound of formula I 3 PolyethyleneGlycol 400 150 acetic acid q.s. ad pH 5.0 water for injection solutionsad 1.0 ml

The invention is illustrated hereinafter by Examples, which have nolimiting character.

In case the preparative examples are obtained as a mixture ofenantiomers, the pure enantiomers can be obtained by methods describedherein or by methods known to those skilled in the art, such as e.g.chiral chromatography or crystallization.

EXAMPLES Intermediate 1: N-tert-Butyl-3-(4-chlorophenyl)-5-iodobenzamide

Step A

To a stirred solution of commercially available 3-iodo-5-nitrobenzoicacid (2 g, 6.83 mmol) in THF (49.1 ml) was added at room temperatureN,N-diisopropylethylamine (2.21 g, 2.98 ml, 17.1 mmol),2-methylpropan-2-amine (611 mg, 878 μl, 8.19 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (3.51 g, 10.9 mmol). The reaction mixture was stirred at roomtemperature for 4 h, evaporated and the residue purified by flashchromatography on silica gel [heptane/ethyl acetate (0-50%)] to yieldN-tert-butyl-3-iodo-5-nitrobenzamide (2.31 g, 97%) as an off-whitesolid, MS (ISP) m/z=349.0 [(M+H)+], mp 166° C.

Step B

A mixture of N-tert-butyl-3-iodo-5-nitrobenzamide (2.3 g, 6.61 mmol) and(4-chlorophenyl)boronic acid (1.34 g, 8.59 mmol) in 1,2-dimethoxyethane(44 ml) and 2M Na₂CO₃ (11 ml, 22 mmol) was purged with argon in anultrasonic bath for 5 min, triphenylphosphine (347 mg, 1.32 mmol) andpalladium(II)acetate (148 mg, 661 μmol) were added and the reactionmixture was stirred for 3 h under reflux conditions. The reactionmixture poured into water (50 ml) and extracted with ethylacetate (2×50ml). The combined organic layers were washed with brine (40 ml), dried(MgSO₄) and evaporated to give the crude product (3.09 g) as brownsolid, which was purified by flash chromatography on silica gel[heptane/ethyl acetate (0-50%)] to yieldN-tert-butyl-3-(4-chlorophenyl)-5-nitrobenzamide (2.38 g, 92%) as abrown solid, MS (ISP) m/z=333.1 [(M+H)+], mp 186° C.

Step C To a stirred solution ofN-tert-butyl-3-(4-chlorophenyl)-5-nitrobenzamide (2.38 g, 6.58 mmol) inMeOH (49.8 ml) was added at room temperature tin(II)chloride dihydrate(5.94 g, 26.3 mmol) and the reaction mixture was stirred under refluxconditions for 2 h, evaporated, water (50 ml) and 2N NaOH (50 ml) wereadded and the mixture was extracted with ethyl acetate (2×75 ml). Thecombined organic layers were washed with water (50 ml) and brine (50ml), dried (MgSO₄) and evaporated. The crude product (brown solid, 2.08g) was purified by flash chromatography on silica gel[dichloromethane/MeOH (1-5%)] to yield3-amino-N-tert-butyl-5-(4-chlorophenyl)-benzamide (1.90 g, 95%) as alight brown solid, MS (ISP) m/z=303.1 [(M+H)+], mp 231° C.

Step D

A mixture of 3-amino-N-tert-butyl-5-(4-chlorophenyl)-benzamide (1.899 g,6.27 mmol), isoamyl nitrite (4.59 g, 5.27 ml, 37.6 mmol) anddiiodomethane (10.2 g, 3.07 ml, 37.6 mmol) was stirred at roomtemperature for 1 h, and afterwards at 65° C. for 5 h. The reactionmixture was cooled to room temperature, toluene (30 ml) was added andthe mixture was evaporated to dryness which was repeated 3 times. Theresidue was purified by flash chromatography on silica gel [heptane/ethyacetate (0-40%)] to yield the title compound (1.41 g, 55%) as lightyellow foam, MS (ISP) m/z=414.0 [(M+H)⁺].

Intermediate 2: N-tert-Butyl-3-(4-fluorophenyl)-5-iodobenzamide

Step A

3-(4-Fluorophenyl)-5-nitrobenzoic acid, light brown solid (4.33 g, 97%),MS (ISN) m/z=260.1 [(M−H)⁻], mp 182° C., was prepared in accordance withthe general method of intermediate 1, step B, from commerciallyavailable 3-iodo-5-nitrobenzoic acid (5.0 g, 17.1 mmol) and commerciallyavailable (4-fluorophenyl)-boronic acid (2.63 g, 18.8 mmol).

Step B

N-tert-Butyl-3-(4-fluorophenyl)-5-nitrobenzamide, yellow solid (1.03 g,93%), MS (ISP) m/z=317.1 [(M+H)⁺], mp 180° C., was prepared inaccordance with the general method of intermediate 1, step A, from3-(4-fluorophenyl)-5-nitrobenzoic acid (914 mg, 3.50 mmol) andcommercially available 2-methylpropan-2-amine (307 mg, 441 μl, 4.20mmol).

Step C

3-Amino-N-tert-butyl-5-(4-fluorophenyl)-benzamide, light yellow solid(0.93 g, 99%), MS (ISP) m/z=287.2 [(M+H)⁺], mp 215° C., was prepared inaccordance with the general method of intermediate 1, step C, fromN-tert-Butyl-3-(4-fluorophenyl)-5-nitrobenzamide (1.03 g, 3.26 mmol).

Step D

The title compound, off-white (0.83 g, 64%), MS (ISP) m/z=398.1[(M+H)⁺], mp 146° C., was prepared in accordance with the general methodof intermediate 1, step D, from3-amino-N-tert-butyl-5-(4-fluorophenyl)-benzamide (0.93 g, 3.25 mmol).

Intermediate 3:N-tert-Butyl-3-iodo-5-[4-(trifluoromethyl)-phenyl]-benzamide

Step A

N-tert-Butyl-3-nitro-5-[4-(trifluoromethyl)-phenyl]-benzamide, lightbrown solid (0.52 g, 99%), MS (ISP) m/z=367.2 [(M+H)⁺], mp 187.5° C.,was prepared in accordance with the general method of intermediate 1,step B, from N-tert-butyl-3-iodo-5-nitrobenzamide (intermediate 1, stepA) (0.50 g, 1.44 mmol) and commercially available(4-trifluoromethyl-phenyl)-boronic acid (355 mg, 1.87 mmol).

Step B

3-Amino-N-tert-butyl-5-[4-(trifluoromethyl)-phenyl]-benzamide, lightyellow solid (0.48 g, 99%), MS (ISP) m/z=337.2 [(M+H)⁺], mp 228.5° C.,was prepared in accordance with the general method of intermediate 1,step C, fromN-tert-butyl-3-nitro-5-[4-(trifluoromethyl)-phenyl]-benzamide (0.52 g,1.42 mmol).

Step C

The title compound, light yellow solid (0.44 g, 72%), MS (ISP) m/z=448.1[(M+H)⁺], mp 139° C., was prepared in accordance with the general methodof intermediate 1, step D, from3-amino-N-tert-butyl-5-[4-(trifluoromethyl)-phenyl]-benzamide (0.46 g,1.37 mmol).

Intermediate 4:N-tert-Butyl-3-iodo-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide

Step A

N-tert-Butyl-3-nitro-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide, off-whitesolid (1.29 g, 78%), MS (ISP) m/z=331.2 [(M+H)⁺], mp 156° C., wasprepared in accordance with the general method of intermediate 1, stepB, from N-tert-butyl-3-iodo-5-nitrobenzamide (intermediate 1, step A)(1.74 g, 5.0 mmol) and commercially available(1-isopropyl-1H-pyrazol-5-yl)-boronic acid (1.0 g, 6.5 mmol).

Step B

3-Amino-N-tert-butyl-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide, whitesolid (1.15 g, 98%), MS (ISP) m/z=301.2 [(M+H)⁺], mp 195° C., wasprepared in accordance with the general method of intermediate 1, stepC, from N-tert-butyl-3-nitro-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide(1.29 g, 3.90 mmol).

Step C

The title compound, light yellow foam (1.23 g, 78%), MS (ISP) m/z=412.2[(M+H)⁺], mp 166° C., was prepared in accordance with the general methodof intermediate 1, step D, from3-amino-N-tert-butyl-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide (1.15 g,3.83 mmol).

Intermediate 5:3-(4-Chlorophenyl)-5-iodo-N-(2-methylbutan-2-yl)-benzamide

Step A

3-Iodo-N-(2-methylbutan-2-yl)-5-nitrobenzamide, off-white solid (1.44 g,99%), MS (ISP) m/z=363.0 [(M+H)⁺], mp 117° C., was prepared inaccordance with the general method of intermediate 1, step A, fromcommercially available 3-iodo-5-nitrobenzoic acid (1.17 g, 4.0 mmol) andcommercially available 2-methylbutan-2-amine (0.42 g, 4.8 mmol).

Step B

3-(4-Chlorophenyl)-N-(2-methylbutan-2-yl)-5-nitrobenzamide, light brownsolid (0.69 g, 99%), MS (ISP) m/z=347.1 [(M+H)⁺], mp 171.5° C., wasprepared in accordance with the general method of intermediate 1, stepB, from 3-iodo-N-(2-methylbutan-2-yl)-5-nitrobenzamide (0.72 g, 1.99mmol) and commercially available (4-chlorophenyl)-boronic acid (405 mg,2.59 mmol).

Step C

3-Amino-5-(4-chlorophenyl)-N-(2-methylbutan-2-yl)-benzamide, lightyellow solid (0.62 g, 97%), MS (ISP) m/z=317.2 [(M+H)⁺], mp 192° C., wasprepared in accordance with the general method of intermediate 1, stepC, from 3-(4-chlorophenyl)-N-(2-methylbutan-2-yl)-5-nitrobenzamide (1.25g, 3.48 mmol).

Step D

The title compound, light yellow solid (0.65 g, 78%), MS (ISP) m/z=428.1[(M+H)⁺], mp 136° C., was prepared in accordance with the general methodof intermediate 1, step D, from3-amino-5-(4-chlorophenyl)-N-(2-methylbutan-2-yl)-benzamide (0.62 g,1.96 mmol).

Intermediate 6:3-(4-Chlorophenyl)-N-(2-cyano-propan-2-yl)-5-iodo-benzamide

Step A

To a stirred solution of commercially available 3-iodo-5-nitrobenzoicacid (3.60 g, 12.3 mmol) and Pd(Ph₃P)₄ (454 mg, 393 μmol) in toluene (68ml) and ethanol (11.3 ml) was added at room temperature commerciallyavailable 4-chloro-phenylboronic acid (2.11 g, 13.5 mmol) and a solutionof Cs₂CO₃ (4.40 g, 13.5 mmol) in water (4.56 ml). The reaction mixturewas stirred under reflux conditions for 18 h and then cooled to roomtemperature. To the mixture was added 2N NaOH (50 ml), and the reactionmixture was stirred for 30 min at room temperature. Some precipitatedmaterial was collected by filtration. The organic layer was separated,and to the water layer together with the precipitated material was addedconc. hydrochloric acid (18 ml) to reach pH<4. The mixture was extractedwith ethyl acetate (2×75 ml), the combined organic layers were washedwith brine, dried (MgSO₄) and evaporated to yield crude3-(4-chlorophenyl)-5-nitrobenzoic acid (3.26 g, 11.7 mmol) as brownsolid, MS (ISN) m/z=276.1 [(M−H)⁻], which was subsequently dissolved inmethanol (29 ml). To the stirred solution was added dropwise thionylchloride (1.54 g, 0.94 ml, 12.9 mmol) at 0° C. The reaction mixture wasallowed to warm to room temperature, and was afterwards stirred underreflux conditions for 2 h. The solvent was removed in vacuo to yieldcrude methyl 3-(4-chlorophenyl)-5-nitrobenzoate (3.26 g, 11.2 mmol) as abrown solid, MS (ISP) m/z=292.1 [(M+H)⁺], which was subsequentlydissolved in methanol (29 ml). To the stirred solution was added at roomtemperature tin(II)chloride (8.48 g, 44.7 mmol), the reaction mixturewas stirred under reflux conditions for 3 h, evaporated, the residue wasdissolved in water (150 ml) and basified to pH=9 by addition of Na₂CO₃.The mixture was extracted with dichloro-methane (3×75 ml), the combinedorganic layers were washed with water (150 ml), brine (150 ml), dried(MgSO₄) and evaporated. The crude product was purified by flashchromatography on silica gel [heptane/ethyl acetate (20-50%)] to yieldmethyl 3-amino-5-(4-chlorophenyl)-benzoate (2.29 g, 71%) as a yellowsolid, MS (ISP) m/z=262.1 [(M+H)⁺], mp 120° C.

Step B

A suspension of methyl 3-amino-5-(4-chlorophenyl)-benzoate (2.45 g, 9.36mmol), isoamyl nitrite (6.85 g, 7.86 ml, 56.2 mmol), copper(I)iodide(1.78 g, 9.36 mmol) and diiodomethane (15.2 g, 4.58 ml, 56.2 mmol) inTHF (24.1 ml) was allowed to stir at room temperature for 1 h hour andafterwards under reflux conditions for 3 h. To the reaction mixture wasadded toluene (30 ml) at room temperature, the mixture was evaporatedand purified by flash chromatography on silica gel [heptane/ethylacetate (0-50%)] to yield methyl 5-(4-chlorophenyl)-3-iodo-benzoate(3.17 g, 91%) as a light yellow solid, MS (ISP) m/z=372.1 [(M+H)⁺], mp90.5° C.

Step C

To a stirred mixture of methyl 5-(4-chlorophenyl)-3-iodo-benzoate (499mg, 1.34 mmol) in THF (2.24 ml), methanol (2.24 ml) and water (2.24 ml)was added at room temperature lithium hydroxide monohydrate (73.1 mg,1.74 mmol). The reaction mixture was allowed to stir for 4 h at roomtemperature, concentrated to one third, 2N HCl solution (2.58 ml) wasadded, the precipitate collected by filtration and dried to yield5-(4-chlorophenyl)-3-iodo-benzoic acid (440 mg, 92%) as an off-whitesolid, MS (ISN) m/z=357.1 [(M−H)⁻], mp 222.5° C.

Step D

The title compound, light yellow oil (0.51 g, 98%), MS (ISP) m/z=425.2[(M+H)⁺], was prepared in accordance with the general method ofintermediate 1, step A, from 5-(4-chlorophenyl)-3-iodo-benzoic acid (441mg, 1.23 mmol) and commercially available2-amino-2-methyl-propanenitrile (155 mg, 169 μl, 1.84 mmol).

Intermediate 7:N-tert-Butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-iodo-benzamide

N-tert-Butyl-3-(2-tert-butylpyrazol-3-yl)-5-nitrobenzamide, yellow solid(1.56 g, 81%), MS (ISP) m/z=345.2 [(M+H)⁺], mp 179.5° C., was preparedin accordance with the general method of intermediate 1, step B, fromN-tert-butyl-3-iodo-5-nitrobenzamide (intermediate 1, step A) (1.95 g,5.6 mmol) and commercially available1-(tert-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.82 g, 7.28 mmol)

Step B

3-Amino-N-tert-butyl-5-(2-tert-butyl-pyrazol-3-yl)-benzamide, off-whitesolid (1.41 g, 100%), MS (ISP) m/z=315.2 [(M+H)⁺], mp 219.5° C., wasprepared in accordance with the general method of intermediate 1, stepC, from N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-nitrobenzamide (1.54g, 4.47 mmol).

Step C

The title compound, off-white solid (1.28 g, 67%), MS (ISP) m/z=426.2[(M+H)⁺], mp 206° C., was prepared in accordance with the general methodof intermediate 1, step D, from3-amino-N-tert-butyl-5-(2-tert-butyl-pyrazol-3-yl)-benzamide (1.42 g,4.52 mmol).

Intermediate 8:3-(4-Chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-iodobenzamide

Step A

3-(4-Chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-nitrobenzamide, lightyellow solid (1.25 g, 92%), MS (ISP) m/z=359.1 [(M+H)⁺], mp 172° C., wasprepared in accordance with the general method of intermediate 1, stepA, from 3-(4-chlorophenyl)-5-nitrobenzoic acid (intermediate 2, step A)(1.05 g, 3.78 mmol) and commercially available2-cyclopropylpropan-2-amine (0.45 g, 4.54 mmol).

Step B

3-Amino-5-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-benzamide, lightyellow solid (0.98 g, 85%), MS (ISP) m/z=329.1 [(M+H)⁺], mp 199° C., wasprepared in accordance with the general method of intermediate 1, stepC, from3-(4-chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-5-nitrobenzamide (1.25g, 3.48 mmol).

Step C

The title compound, light brown solid (1.0 g, 77%), MS (ISP) m/z=440.1[(M+H)⁺], mp 152° C., was prepared in accordance with the general methodof intermediate 1, step D, from3-amino-5-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-benzamide (0.97g, 2.95 mmol).

Intermediate 9:3-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-iodo-benzamide

Step A

3-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-nitrobenzamide,light yellow foam (1.36 g, 72%), MS (ISP) m/z=349.1 [(M+H)⁺], wasprepared in accordance with the general method of intermediate 1, stepA, from 3-(4-chlorophenyl)-5-nitrobenzoic acid (intermediate 2, step A)(1.50 g, 5.40 mmol) and commercially available2-amino-2-methylpropan-1-ol (0.58 g, 6.48 mmol).

Step B

3-Amino-5-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-benzamide,light yellow foam (0.54 g, 99%), MS (ISP) m/z=319.2 [(M+H)⁺], mp 150°C., was prepared in accordance with the general method of intermediate1, step C, from3-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-nitrobenzamide(0.60 g, 1.72 mmol).

Step C

The title compound, light yellow foam (0.52 g, 74%), MS (ISP) m/z=430.1[(M+H)⁺], mp 79° C., was prepared in accordance with the general methodof intermediate 1, step D, from3-amino-5-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-benzamide(0.52 g, 1.63 mmol).

Intermediate 10:3-(4-Chlorophenyl)-5-iodo-N-(1,1,1-trifluoro-2-methyl-propan-2-yl)-benzamide

Step A

3-(4-Chlorophenyl)-5-nitro-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide,off-white solid (0.63 g, 43%), MS (ISP) m/z=387.1 [(M+H)⁺], mp 180° C.,was prepared in accordance with the general method of intermediate 1,step A, from 3-(4-chlorophenyl)-5-nitrobenzoic acid (intermediate 2,stepA) (1.05 g, 3.78 mmol) and commercially available1,1,1-trifluoro-2-methylpropan-2-amine (577 mg, 4.54 mmol).

Step B

3-Amino-5-(4-chlorophenyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide,light yellow solid (0.57 g, 98%), MS (ISP) m/z=357.1 [(M+H)⁺], mp 150°C., was prepared in accordance with the general method of intermediate1, step C, from3-(4-chlorophenyl)-5-nitro-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide(0.63 g, 1.63 mmol).

Step C

The title compound, light yellow solid (0.53 g, 71%), MS (ISP) m/z=468.1[(M+H)⁺], mp 163° C., was prepared in accordance with the general methodof intermediate 1, step D, from3-amino-5-(4-chlorophenyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide(0.56 g, 1.58 mmol).

Example 1:N-tert-Butyl-3-(4-chlorophenyl)-5-(2-methyl-pyrazol-3-yl)-benzamide

In a sealed tube a mixture ofN-tert-butyl-3-(4-chlorophenyl)-5-iodobenzamide (intermediate 1) (103mg, 0.25 mmol), commercially available1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(67.6 mg, 325 μmol), 1,2-dimethoxyethane (1.67 ml) and 2M sodiumcarbonate solution (416 μl, 833 μmol) was purged with argon in anultrasonic bath for 5 min, triphenylphosphine (13.1 mg, 50 μmol) andpalladium(II)acetate (5.61 mg, 25 μmol) were added and the reactionmixture was allowed to stir for 16 h at 105° C. The crude reactionmixture was purified by flash chromatography on silica gel[heptane/ethyl acetate (10-60%)] to yield the title compound (73 mg,79%) as a light brown solid, MS (ISP) m/z=368.2 [(M+H)⁺], mp 191° C.

Example 2:N-tert-Butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-(4-fluorophenyl)-benzamide

The title compound, white solid (61 mg, 62%), MS (ISP) m/z=394.4[(M+H)⁺], mp 210° C., was prepared in accordance with the general methodof example 1 from N-tert-butyl-3-(4-fluorophenyl)-5-iodobenzamide(intermediate 2) (99.3 mg, 0.25 mmol) and commercially available1-(tert-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(75.0 mg, 0.30 mmol).

Example 3:N-tert-Butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

The title compound, off-white solid (63 mg, 57%), MS (ISP) m/z=444.4[(M+H)⁺], mp 205° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-iodo-5-[4-(trifluoromethyl)-phenyl]-benzamide(intermediate 3) (112 mg, 0.25 mmol) and commercially available1-(tert-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(75.0 mg, 0.30 mmol).

Example 4:N-tert-Butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-(4-chlorophenyl)-benzamide

The title compound, white solid (39 mg, 34%), MS (ISP) m/z=410.3[(M+H)⁺], mp 209° C., was prepared in accordance with the general methodof example 1 from N-tert-butyl-3-(4-chlorophenyl)-5-iodobenzamide(intermediate 1) (103 mg, 0.25 mmol) and commercially available1-(tert-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(75.0 mg, 0.30 mmol).

Example 5:N-tert-Butyl-3-(4-chlorophenyl)-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide

The title compound, white foam (70 mg, 71%), MS (ISP) m/z=396.3[(M+H)⁺], mp 84° C., was prepared in accordance with the general methodof example 1 from N-tert-butyl-3-(4-chlorophenyl)-5-iodobenzamide(intermediate 1) (103 mg, 0.25 mmol) and commercially available(1-isopropyl-1H-pyrazol-5-yl)-boronic acid (46.2 mg, 300 μmol).

Example 6:N-tert-Butyl-3-(4-fluorophenyl)-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide

The title compound, light yellow solid (91 mg, 96%), MS (ISP) m/z=380.3[(M+H)⁺], mp 161° C., was prepared in accordance with the general methodof example 1 from N-tert-butyl-3-(4-fluorophenyl)-5-iodobenzamide(intermediate 2) (99.3 mg, 0.25 mmol) and commercially available(1-isopropyl-1H-pyrazol-5-yl)-boronic acid (50.0 mg, 325 μmol).

Example 7:N-tert-Butyl-3-(2-propan-2-yl-pyrazol-3-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

The title compound, off-white foam (104 mg, 97%), MS (ISP) m/z=430.3[(M+H)⁺], mp 81° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-iodo-5-[4-(trifluoromethyl)-phenyl]-benzamide(intermediate 3) (112 mg, 0.25 mmol) and commercially available(1-isopropyl-1H-pyrazol-5-yl)-boronic acid (50.0 mg, 325 μmol).

Example 8:N-tert-Butyl-3-(3,4-difluorophenyl)-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide

The title compound, off-white solid (95 mg, 96%), MS (ISP) m/z=398.3.3[(M+H)⁺], mp 82° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-iodo-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide(intermediate 4) (103 mg, 0.25 mmol) and commercially available(3,4-difluorophenyl)-boronic acid (51.3 mg, 325 μmol).

Example 9:N-tert-Butyl-3-(4-methylphenyl)-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide

The title compound, light yellow solid (88 mg, 94%), MS (ISP) m/z=376.3[(M+H)⁺], mp 163° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-iodo-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide(intermediate 4) (103 mg, 0.25 mmol) and commercially availablep-tolyl-boronic acid (44.2 mg, 325 μmol).

Example 10:N-tert-Butyl-3-(4-propan-2-yl-phenyl)-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide

The title compound, white foam (96 mg, 95%), MS (ISP) m/z=404.3[(M+H)⁺], mp 86° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-iodo-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide(intermediate 4) (103 mg, 0.25 mmol) and commercially available(4-isopropylphenyl)-boronic acid (53.3 mg, 325 μmol).

Example 11:N-tert-Butyl-3-(4-methoxyphenyl)-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide

The title compound, light brown foam (96 mg, 98%), MS (ISP) m/z=392.3[(M+H)⁺], mp 79° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-iodo-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide(intermediate 4) (103 mg, 0.25 mmol) and commercially available(4-methoxyphenyl)-boronic acid (49.4 mg, 325 μmol).

Example 12:N-tert-Butyl-3-(3-chloro-4-fluorophenyl)-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide

The title compound, off-white foam (103 mg, 99%), MS (ISP) m/z=414.2[(M+H)⁺], mp 81° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-iodo-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide(intermediate 4) (103 mg, 0.25 mmol) and commercially available(3-chloro-4-fluoro-phenyl)-boronic acid (56.7 mg, 325 μmol).

Example 13:N-tert-Butyl-3-phenyl-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide

The title compound, light red solid (86 mg, 95%), MS (ISP) m/z=362.3[(M+H)⁺], mp 168° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-iodo-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide(intermediate 4) (103 mg, 0.25 mmol) and commercially availablephenyl-boronic acid (39.6 mg, 325 μmol).

Example 14:N-tert-Butyl-3-(4-cyclopropyl-phenyl)-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide

The title compound, off-white foam (96 mg, 96%), MS (ISP) m/z=402.3[(M+H)⁺], mp 83° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-iodo-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide(intermediate 4) (103 mg, 0.25 mmol) and commercially available(4-cyclopropyl-phenyl)-boronic acid (52.6 mg, 325 μmol).

Example 15:N-tert-Butyl-3-(4-fluoro-3-methyl-phenyl)-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide

The title compound, off-white solid (85 mg, 86%), MS (ISP) m/z=394.3[(M+H)⁺], mp 155° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-iodo-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide(intermediate 4) (103 mg, 0.25 mmol) and commercially available(4-fluoro-3-methyl-phenyl)-boronic acid (50.0 mg, 325 μmol).

Example 16:N-tert-Butyl-3-(4-chloro-3-fluoro-phenyl)-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide

The title compound, off-white foam (98 mg, %), MS (ISP) m/z=414.2[(M+H)⁺], mp 87° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-iodo-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide(intermediate 4) (103 mg, 0.25 mmol) and commercially available(4-chloro-3-fluoro-phenyl)-boronic acid (56.7 mg, 325 μmol).

Example 17:N-tert-Butyl-3-(4-cyano-phenyl)-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide

The title compound, light red foam (91 mg, %), MS (ISP) m/z=387.2[(M+H)⁺], mp 94° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-iodo-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide(intermediate 4) (103 mg, 0.25 mmol) and commercially available(4-cyano-phenyl)-boronic acid (47.8 mg, 325 μmol).

Example 18:3-(2-tert-Butyl-pyrazol-3-yl)-5-(4-chlorophenyl)-N-(2-methyl-butan-2-yl)-benzamide

The title compound, white solid (40 mg, 38%), MS (ISP) m/z=424.3[(M+H)⁺], mp 183.5° C., was prepared in accordance with the generalmethod of example 1 from3-(4-chlorophenyl)-5-iodo-N-(2-methylbutan-2-yl)-benzamide (intermediate5) (107 mg, 0.25 mmol) and commercially available1-(tert-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(81.3 mg, 325 μmol).

Example 19:3-(4-Chlorophenyl)-N-(2-methyl-butan-2-yl)-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide

The title compound, white foam (80 mg, 78%), MS (ISP) m/z=410.2[(M+H)⁺], mp 72.5° C., was prepared in accordance with the generalmethod of example 1 from3-(4-chlorophenyl)-5-iodo-N-(2-methylbutan-2-yl)-benzamide (intermediate5) (107 mg, 0.25 mmol) and commercially available(1-isopropyl-1H-pyrazol-5-yl)-boronic acid (50.0 mg, 325 μmol).

Example 20:N-tert-Butyl-3-(3-fluoro-4-methyl-phenyl)-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide

The title compound, light red foam (93 mg, 95%), MS (ISP) m/z=394.3[(M+H)⁺], mp 81° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-iodo-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide(intermediate 4) (103 mg, 0.25 mmol) and commercially available(3-fluoro-4-methyl-phenyl)-boronic acid (50.0 mg, 325 μmol).

Example 21:3-(4-Chlorophenyl)-N-(2-cyano-propan-2-yl)-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide

The title compound, light yellow foam (80 mg, 79%), MS (ISP) m/z=407.2[(M+H)⁺], mp 96° C., was prepared in accordance with the general methodof example 1 from3-(4-chlorophenyl)-N-(2-cyano-propan-2-yl)-5-iodo-benzamide(intermediate 6) (106 mg, 0.25 mmol) and commercially available(1-isopropyl-1H-pyrazol-5-yl)-boronic acid (50.0 mg, 325 μmol).

Example 22:3-(2-tert-Butylpyrazol-3-yl)-5-(4-chlorophenyl)-N-(2-cyanopropan-2-yl)-benzamide

The title compound, white foam (70 mg, 67%), MS (ISP) m/z=421.3[(M+H)⁺], mp 119° C., was prepared in accordance with the general methodof example 1 from3-(4-chlorophenyl)-N-(2-cyano-propan-2-yl)-5-iodo-benzamide(intermediate 6) (106 mg, 0.25 mmol) and commercially available1-(tert-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(81.3 mg, 325 μmol).

Example 23:N-tert-Butyl-3-(2-cyclopropyl-pyrazol-3-yl)-5-(4-fluorophenyl)-benzamide

The title compound, white foam (70 mg, 74%), MS (ISP) m/z=378.3[(M+H)⁺], mp 66° C., was prepared in accordance with the general methodof example 1 from N-tert-butyl-3-(4-fluorophenyl)-5-iodobenzamide(intermediate 2) (99.3 mg, 0.25 mmol) and commercially available1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(76.1 mg, 325 μmol).

Example 24:N-tert-Butyl-3-(4-chlorophenyl)-5-(2-ethyl-pyrazol-3-yl)-benzamide

The title compound, off-white foam (74 mg, 78%), MS (ISP) m/z=382.2[(M+H)⁺], mp 68° C., was prepared in accordance with the general methodof example 1 from N-tert-butyl-3-(4-chlorophenyl)-5-iodobenzamide(intermediate 1) (103 mg, 0.25 mmol) and commercially available(1-ethyl-1H-pyrazol-5-yl)-boronic acid (45.5 mg, 325 μmol).

Example 25:N-tert-Butyl-3-(4-chlorophenyl)-5-[2-(cyclopropyl-methyl)-pyrazol-3-yl]-benzamide

The title compound, white solid (84 mg, 82%), MS (ISP) m/z=408.2[(M+H)⁺], mp 159° C., was prepared in accordance with the general methodof example 1 from N-tert-butyl-3-(4-chlorophenyl)-5-iodobenzamide(intermediate 1) (103 mg, 0.25 mmol) and commercially available1-(cyclopropylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(80.6 mg, 325 μmol).

Example 26:3-(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide

The title compound, light yellow foam (99 mg, 94%), MS (ISP) m/z=422.3[(M+H)⁺], mp 169° C., was prepared in accordance with the general methodof example 1 from3-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-iodobenzamide(intermediate 8) (110 mg, 0.25 mmol) and commercially available(1-isopropyl-1H-pyrazol-5-yl)-boronic acid (50.0 mg, 325 μmol).

Example 27:N-tert-Butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-(4-fluoro-3-methyl-phenyl)-benzamide

The title compound, white solid (61 mg, 60%), MS (ISP) m/z=408.3[(M+H)⁺], mp 186° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-iodo-benzamide(intermediate 7) (106 mg, 0.25 mmol) and commercially available(4-fluoro-3-methyl-phenyl)-boronic acid (50.0 mg, 325 μmol).

Example 28:N-tert-Butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-phenyl-benzamide

The title compound, white solid (56 mg, 60%), MS (ISP) m/z=376.3[(M+H)⁺], mp 199.5° C., was prepared in accordance with the generalmethod of example 1 fromN-tert-butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-iodo-benzamide(intermediate 7) (106 mg, 0.25 mmol) and commercially availablephenyl-boronic acid (39.6 mg, 325 μmol).

Example 29:N-tert-Butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-(3-fluoro-4-methyl-phenyl)-benzamide

The title compound, white solid (65 mg, 64%), MS (ISP) m/z=408.3[(M+H)⁺], mp 202° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-iodo-benzamide(intermediate 7) (106 mg, 0.25 mmol) and commercially available(3-fluoro-4-methyl-phenyl)-boronic acid (50.0 mg, 325 μmol).

Example 30:N-tert-Butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-(4-methyl-phenyl)-benzamide

The title compound, white solid (57 mg, 59%), MS (ISP) m/z=390.3[(M+H)⁺], mp 193° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-iodo-benzamide(intermediate 7) (106 mg, 0.25 mmol) and commercially availablep-tolyl-boronic acid (44.2 mg, 325 μmol).

Example 31:N-tert-Butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-(4-methoxy-phenyl)-benzamide

The title compound, white solid (68 mg, 67%), MS (ISP) m/z=406.3[(M+H)⁺], mp 173° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-iodo-benzamide(intermediate 7) (106 mg, 0.25 mmol) and commercially available(4-methoxyphenyl)-boronic acid (49.4 mg, 325 μmol).

Example 32:N-tert-Butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-(3-chloro-4-fluoro-phenyl)-benzamide

The title compound, white solid (52 mg, 49%), MS (ISP) m/z=428.3[(M+H)⁺], mp 175° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-iodo-benzamide(intermediate 7) (106 mg, 0.25 mmol) and commercially available(3-chloro-4-fluoro-phenyl)-boronic acid (56.7 mg, 325 μmol).

Example 33:N-tert-Butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-(4-chloro-3-fluoro-phenyl)-benzamide

The title compound, white solid (69 mg, 65%), MS (ISP) m/z=428.3[(M+H)⁺], mp 225° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-iodo-benzamide(intermediate 7) (106 mg, 0.25 mmol) and commercially available(4-chloro-3-fluoro-phenyl)-boronic acid (56.7 mg, 325 μmol).

Example 34:N-tert-Butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-(4-propan-2-yl-phenyl)-benzamide

The title compound, white solid (64 mg, 61%), MS (ISP) m/z=418.4[(M+H)⁺], mp 209.5° C., was prepared in accordance with the generalmethod of example 1 fromN-tert-butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-iodo-benzamide(intermediate 7) (106 mg, 0.25 mmol) and commercially available(4-isopropylphenyl)-boronic acid (53.3 mg, 325 μmol).

Example 35:3-(2-tert-Butyl-pyrazol-3-yl)-5-(4-chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-benzamide

The title compound, yellow solid (48 mg, 44%), MS (ISP) m/z=436.3[(M+H)⁺], mp 166° C., was prepared in accordance with the general methodof example 1 from3-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-iodobenzamide(intermediate 8) (110 mg, 0.25 mmol) and commercially available1-(tert-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(81.3 mg, 325 μmol).

Example 36:N-tert-Butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-(3,4-difluorophenyl)-benzamide

The title compound, white solid (53 mg, 52%), MS (ISP) m/z=412.3[(M+H)⁺], mp 197.5° C., was prepared in accordance with the generalmethod of example 1 fromN-tert-butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-iodo-benzamide(intermediate 7) (106 mg, 0.25 mmol) and commercially available(3,4-difluorophenyl)-boronic acid (51.3 mg, 325 μmol).

Example 37:N-tert-Butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-(4-cyclopropyl-phenyl)-benzamide

The title compound, white solid (60 mg, 58%), MS (ISP) m/z=416.3[(M+H)⁺], mp 198.5° C., was prepared in accordance with the generalmethod of example 1 fromN-tert-butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-iodo-benzamide(intermediate 7) (106 mg, 0.25 mmol) and commercially available(4-cyclopropyl-phenyl)-boronic acid (52.6 mg, 325 μmol).

Example 38:N-tert-Butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-(4-cyano-phenyl)-benzamide

The title compound, white solid (63 mg, 63%), MS (ISP) m/z=401.3[(M+H)⁺], mp 201.5° C., was prepared in accordance with the generalmethod of example 1 fromN-tert-butyl-3-(2-tert-butyl-pyrazol-3-yl)-5-iodo-benzamide(intermediate 7) (106 mg, 0.25 mmol) and commercially available(4-cyano-phenyl)-boronic acid (47.8 mg, 325 μmol).

Example 39:3-(4-Chlorophenyl)-N-(1-hydroxy-2-methyl-propan-2-yl)-5-(2-propan-2-yl-pyrazol-3-yl)-benzamide

The title compound, off-white foam (80 mg, 78%), MS (ISP) m/z=412.3[(M+H)⁺], mp 80.5° C., was prepared in accordance with the generalmethod of example 1 from3-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-iodo-benzamide(intermediate 9) (107 mg, 0.25 mmol) and commercially available(1-isopropyl-1H-pyrazol-5-yl)-boronic acid (50.0 mg, 325 μmol).

Example 40:3-(4-Chlorophenyl)-5-(2-propan-2-yl-pyrazol-3-yl)-N-(1,1,1-trifluoro-2-methyl-propan-2-yl)-benzamide

The title compound, off-white foam (90 mg, 80%), MS (ISP) m/z=450.2[(M+H)⁺], mp 77.5° C., was prepared in accordance with the generalmethod of example 1 from3-(4-chlorophenyl)-5-iodo-N-(1,1,1-trifluoro-2-methyl-propan-2-yl)-benzamide(intermediate 10) (117 mg, 0.25 mmol) and commercially available(1-isopropyl-1H-pyrazol-5-yl)-boronic acid (50.0 mg, 325 μmol).

Example 41:3-(2-tert-Butyl-pyrazol-3-yl)-5-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-benzamide

The title compound, off-white foam (60 mg, 56%), MS (ISP) m/z=426.3[(M+H)⁺], mp 83° C., was prepared in accordance with the general methodof example 1 from3-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-iodo-benzamide(intermediate 9) (107 mg, 0.25 mmol) and commercially available1-(tert-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(81.3 mg, 325 μmol).

Example 42:3-(2-tert-Butylpyrazol-3-yl)-5-(4-chlorophenyl)-N-(1,1,1-trifluoro-2-methyl-propan-2-yl)-benzamide

The title compound, light yellow foam (30 mg, 26%), MS (ISP) m/z=464.4[(M+H)⁺], mp 81° C., was prepared in accordance with the general methodof example 1 from3-(4-chlorophenyl)-5-iodo-N-(1,1,1-trifluoro-2-methyl-propan-2-yl)-benzamide(intermediate 10) (117 mg, 0.25 mmol) and commercially available1-(tert-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(81.3 mg, 325 μmol).

Example 43:N-tert-Butyl-3-(2-cyclopropyl-pyrazol-3-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

The title compound, white foam (85 mg, 80%), MS (ISP) m/z=428.3[(M+H)⁺], mp 72° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-iodo-5-[4-(trifluoromethyl)-phenyl]-benzamide(intermediate 3) (112 mg, 0.25 mmol) and commercially available1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(76.1 mg, 325 μmol).

Example 44:N-tert-Butyl-3-[2-(cyclopropylmethyl)-pyrazol-3-yl]-5-[4-(trifluoromethyl)-phenyl]-benzamide

The title compound, white foam (87 mg, 79%), MS (ISP) m/z=442.3[(M+H)⁺], mp 69° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-iodo-5-[4-(trifluoromethyl)-phenyl]-benzamide(intermediate 3) (112 mg, 0.25 mmol) and commercially available1-(cyclopropylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(80.6 mg, 325 μmol).

Example 45:N-tert-Butyl-3-(4-chlorophenyl)-5-(2-cyclopropyl-pyrazol-3-yl)-benzamide

The title compound, off-white foam (55 mg, 72%), MS (ISP) m/z=394.2[(M+H)⁺], mp 72° C., was prepared in accordance with the general methodof example 1 from N-tert-butyl-3-(4-chlorophenyl)-5-iodobenzamide(intermediate 1) (80.0 mg, 0.19 mmol) and commercially available1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(58.9 mg, 0.25 mmol).

Example 46:N-tert-Butyl-3-[2-(cyclopropylmethyl)-pyrazol-3-yl]-5-(4-fluorophenyl)-benzamide

The title compound, white solid (90 mg, 92%), MS (ISP) m/z=392.3[(M+H)⁺], mp 188° C., was prepared in accordance with the general methodof example 1 from N-tert-butyl-3-(4-fluorophenyl)-5-iodobenzamide(intermediate 2) (99.3 mg, 0.25 mmol) and commercially available1-(cyclopropylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(80.6 mg, 325 μmol).

Example 47:N-tert-Butyl-3-(2-ethyl-pyrazol-3-yl)-5-(4-fluorophenyl)-benzamide

The title compound, off-white solid (87 mg, 95%), MS (ISP) m/z=366.2[(M+H)⁺], mp 162° C., was prepared in accordance with the general methodof example 1 from N-tert-butyl-3-(4-fluorophenyl)-5-iodobenzamide(intermediate 2) (99.3 mg, 0.25 mmol) and commercially available(1-ethyl-1H-pyrazol-5-yl)boronic (45.5 mg, 325 μmol).

Example 48:N-tert-Butyl-3-(2-ethyl-pyrazol-3-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide

The title compound, white foam (67 mg, 65%), MS (ISP) m/z=416.3[(M+H)⁺], mp 70° C., was prepared in accordance with the general methodof example 1 fromN-tert-butyl-3-iodo-5-[4-(trifluoromethyl)-phenyl]-benzamide(intermediate 3) (112 mg, 0.25 mmol) and commercially available(1-ethyl-1H-pyrazol-5-yl)boronic (45.5 mg, 325 μmol).

1. A compound of formula (I):

wherein R^(1′) is methyl; R¹ is selected from the group consisting of i)methyl, ii) ethyl, iii) trifluoromethyl iv) hydroxymethyl, v)cyclopropyl, and vi) cyano; or R^(1′) and R¹ together with the carbonatom to which they are attached form 1,1-dioxo-tetrahydro-thiophen-3-yl;R² is selected from the group consisting of i) hydrogen, ii) methyl,iii) ethyl, iv) isopropyl, v) tert-butyl, vi) cyclopropyl, vii)cyclopropylmethyl, and viii) hydroxymethyl; R³ is selected from thegroup consisting of i) hydrogen, ii) chloro, iii) fluoro, iv) methyl v)isopropyl, vi) methoxy, vii) cyano, viii) cyclopropyl, and ix)trifluoromethyl; R⁴ is selected from the group consisting of i)hydrogen, ii) chloro, iii) fluoro, and iv) methyl; or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1, wherein R¹is methyl.
 3. A compound according to claim 1, wherein R² is selectedfrom the group consisting of i) methyl, ii) ethyl, iii) isopropyl, iv)tert-butyl, v) cyclopropyl, and vi) cyclopropylmethyl.
 4. A compoundaccording to claim 1, wherein R³ is selected from the group consistingof i) hydrogen, ii) chloro, iii) fluoro, iv) methyl v) isopropyl, vi)methoxy, vii) cyano, viii) cyclopropyl, and ix) trifluoromethyl.
 5. Acompound according to claim 1, wherein R³ is selected from the groupconsisting of i) chloro, ii) fluoro, iii) cyano, and iv)trifluoromethyl.
 6. A compound according to claim 1, wherein R⁴ is H. 7.A compound according to claim 1, wherein R^(1′) and R¹ are both methyl;R² is selected from the group consisting of i) methyl, ii) ethyl, iii)isopropyl, iv) tert-butyl, v) cyclopropyl, and vi) cyclopropylmethyl; R³is selected from the group consisting of i) hydrogen, ii) chloro, iii)fluoro, iv) methyl v) isopropyl, vi) methoxy, vii) cyano, and viii)cyclopropyl R⁴ is selected from the group consisting of i) hydrogen, ii)chloro, iii) fluoro, and iv) methyl; or pharmaceutically acceptablesalts.
 8. A compound according to claim 1, selected fromN-tert-butyl-3-(4-chlorophenyl)-5-(2-methylpyrazol-3-yl)benzamide;N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-fluorophenyl)benzamide;N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-[4-(trifluoromethyl)phenyl]benzamide;N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-chlorophenyl)benzamide;N-tert-butyl-3-(4-chlorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;N-tert-butyl-3-(4-fluorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;N-tert-butyl-3-(2-propan-2-ylpyrazol-3-yl)-5-[4-(trifluoromethyl)phenyl]benzamide;N-tert-butyl-3-(3,4-difluorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;N-tert-butyl-3-(4-methylphenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;N-tert-butyl-3-(4-propan-2-ylphenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;N-tert-butyl-3-(4-methoxyphenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;N-tert-butyl-3-(3-chloro-4-fluorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;N-tert-butyl-3-phenyl-5-(2-propan-2-ylpyrazol-3-yl)benzamide;N-tert-butyl-3-(4-cyclopropylphenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;N-tert-butyl-3-(4-fluoro-3-methylphenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;N-tert-butyl-3-(4-chloro-3-fluorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;N-tert-butyl-3-(4-cyanophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;3-(2-tert-butylpyrazol-3-yl)-5-(4-chlorophenyl)-N-(2-methylbutan-2-yl)benzamide;3-(4-chlorophenyl)-N-(2-methylbutan-2-yl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;N-tert-butyl-3-(3-fluoro-4-methylphenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;3-(4-chlorophenyl)-N-(2-cyanopropan-2-yl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;3-(2-tert-butylpyrazol-3-yl)-5-(4-chlorophenyl)-N-(2-cyanopropan-2-yl)benzamide;N-tert-butyl-3-(2-cyclopropylpyrazol-3-yl)-5-(4-fluorophenyl)benzamide;N-tert-butyl-3-(4-chlorophenyl)-5-(2-ethylpyrazol-3-yl)benzamide;N-tert-butyl-3-(4-chlorophenyl)-5-[2-(cyclopropylmethyl)pyrazol-3-yl]benzamide;3-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-fluoro-3-methylphenyl)benzamide;N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-phenylbenzamide;N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(3-fluoro-4-methylphenyl)benzamide;N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-methylphenyl)benzamide;N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-methoxyphenyl)benzamide;N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(3-chloro-4-fluorophenyl)benzamide;N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-chloro-3-fluorophenyl)benzamide;N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-propan-2-ylphenyl)benzamide;3-(2-tert-butylpyrazol-3-yl)-5-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)benzamide;N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(3,4-difluorophenyl)benzamide;N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-cyclopropylphenyl)benzamide;N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-cyanophenyl)benzamide;3-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;3-(4-chlorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide;3-(2-tert-butylpyrazol-3-yl)-5-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)benzamide;3-(2-tert-butylpyrazol-3-yl)-5-(4-chlorophenyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide;N-tert-butyl-3-(2-cyclopropylpyrazol-3-yl)-5-[4-(trifluoromethyl)phenyl]benzamide;N-tert-butyl-3-[2-(cyclopropylmethyl)pyrazol-3-yl]-5-[4-(trifluoromethyl)phenyl]benzamide;N-tert-butyl-3-(4-chlorophenyl)-5-(2-cyclopropylpyrazol-3-yl)benzamide;N-tert-butyl-3-[2-(cyclopropylmethyl)pyrazol-3-yl]-5-(4-fluorophenyl)benzamide;N-tert-butyl-3-(2-ethylpyrazol-3-yl)-5-(4-fluorophenyl)benzamide;N-tert-butyl-3-(2-ethylpyrazol-3-yl)-5-[4-(trifluoromethyl)phenyl]benzamide;or a pharmaceutically acceptable salt thereof.
 9. A compound accordingto claim 1, selected fromN-tert-butyl-3-(4-chlorophenyl)-5-(2-methylpyrazol-3-yl)benzamide;N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-fluorophenyl)benzamide;N-tert-butyl-3-(4-chlorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;N-tert-butyl-3-(4-fluorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;N-tert-butyl-3-(2-propan-2-ylpyrazol-3-yl)-5-[4-(trifluoromethyl)phenyl]benzamide;N-tert-butyl-3-(2-cyclopropylpyrazol-3-yl)-5-(4-fluorophenyl)benzamide;N-tert-butyl-3-(4-chlorophenyl)-5-(2-ethylpyrazol-3-yl)benzamide;N-tert-butyl-3-(4-chlorophenyl)-5-[2-(cyclopropylmethyl)pyrazol-3-yl]benzamide;N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-cyanophenyl)benzamide;N-tert-butyl-3-(4-chlorophenyl)-5-(2-cyclopropylpyrazol-3-yl)benzamide;N-tert-butyl-3-(2-ethylpyrazol-3-yl)-5-(4-fluorophenyl)benzamide; or apharmaceutically acceptable salt thereof.
 10. A process to prepare acompound according to claim 1 comprising a) the reaction of a compoundof formula (II) in the presence of a compound of formula (III), whereinR¹, R^(1′), R², R³ and R⁴ are as defined in any one of claim 1 to 9;

or b) the reaction of a compound of formula (IV) in the presence of acompound of formula (V), wherein R¹, R^(1′), R², R³ and R⁴ are asdefined in any one of claim 1 to 9;

or c) the reaction of a compound of formula (XVII) in the presence of acompound of formula (VII), wherein R¹, R^(1′), R², R³ and R⁴ are asdefined in any one of claim 1 to 9;

or d) the reaction of a compound of formula (XVIII) in the presence of acompound of formula (XVI), wherein R¹, R^(1′), R², R³ and R⁴ are asdefined in any one of claim 1 to
 9.


11. (canceled)
 12. A pharmaceutical composition comprising a compoundaccording to claim 1 and a therapeutically inert carrier.
 13. (canceled)14. (canceled)
 15. (canceled)
 16. A method for the treatment of ocularconditions, which method comprises administering an effective amount ofa compound according to claim
 1. 17. A compound manufactured accordingto a process of claim
 10. 18. (canceled)